Peripheral nervous system disorder

Summary

Peripheral nervous system disorder (MONDO:0003620) is a disease (an umbrella term covering 18 Mondo subtypes) with 2 cohort genes (8 GWAS associations across 18 studies) and 295 clinical trials. Top therapeutic interventions include amitriptyline, capsaicin, and glutamine.

At a glance

• Umbrella term: 18 Mondo subtypes
• Cohort genes: 2
• GWAS associations: 8
• ClinVar variants: 2
• Clinical trials: 295

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	peripheral nervous system disorder
Mondo ID	MONDO:0003620
EFO	EFO:0009387
MeSH	D010523
DOID	DOID:574
NCIT	C27580
SNOMED CT	42658009
UMLS	C4025831
MedGen	892389
Anatomy (UBERON)	UBERON:0000010
Is cancer (heuristic)	no

Also known as: disease of peripheral nervous system · disease or disorder of peripheral nervous system · disorder of peripheral nervous system · disorder of the peripheral nervous system · nerve disease, peripheral · nerve diseases, peripheral · neuropathy, peripheral · peripheral nerve disease · peripheral nerve diseases · peripheral nervous system disease · peripheral nervous system disease or disorder · peripheral nervous system disorder · peripheral nervous system disorders · peripheral Neuropathies · peripheral neuropathy · PNS (peripheral nervous system) diseases · PNS disease · PNS diseases

Data availability: 2 ClinVar variants · 8 GWAS associations (18 studies).

Disease family

An umbrella term covering 18 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder

Related subtypes (71): congenital nervous system disorder, central nervous system disorder, autoimmune disorder of the nervous system, cranial nerve neuropathy, neuronitis, diplegia of upper limb, retinal disorder, developmental disability, restless legs syndrome, movement disorder, toxic encephalopathy, Barre-Lieou syndrome, Gerstmann syndrome, drug-induced akathisia, drug-induced dyskinesia, stiff-person syndrome, Worster-Drought syndrome, corneal-cerebellar syndrome, pachygyria-intellectual disability-epilepsy syndrome, porencephaly-cerebellar hypoplasia-internal malformations syndrome, symmetrical thalamic calcifications, neonatal brainstem dysfunction, primary orthostatic hypotension, rippling muscle disease with myasthenia gravis, periodic paralysis, qualitative or quantitative protein defects in neuromuscular diseases, specific learning disability, cerebellar hypoplasia-tapetoretinal degeneration syndrome, locked-in syndrome, dopa-responsive dystonia, idiopathic recurrent stupor, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, spontaneous periodic hypothermia, Sydenham chorea, duplication of the pituitary gland, Balint syndrome, paraneoplastic neurologic syndrome, persistent idiopathic facial pain, serotonin syndrome, hypothalamic adipsic hypernatraemia syndrome, exercise-induced malignant hyperthermia, perineural cyst, neuromuscular disease, neuromyelitis optica, AL amyloidosis, AA amyloidosis, neuroleptic malignant syndrome, infectious disorder of the nervous system, central nervous system malformation, synaptopathy, nervous system neoplasm, sensory ganglionopathy, radiculitis, wet beriberi, perceptual disorders, prepubertal anorexia nervosa, neurocutaneous syndrome, neurovascular disorder, Wallerian degeneration, nervous system injury, neurosarcoidosis, neuroendocrine disorder, tubulinopathy, atactic disorder, hereditary neurological disease, meningitis-retention syndrome, KIF1A related neurological disorder, neurological pain disorder, neurodevelopmental disorder, post 5-alpha-reductase inhibitors treatment syndrome, post-selective serotonin reuptake inhibitor sexual dysfunction

Subtypes (18): autoimmune disorder of peripheral nervous system, autonomic nervous system disorder, peripheral nervous system neoplasm, vestibulocochlear nerve disorder, hypoglossal nerve disorder, facial nerve disorder, neuroma, accessory nerve disorder, glossopharyngeal nerve disorder, olfactory nerve disorder, radiculopathy, trigeminal nerve disorder, third cranial nerve disorder, peripheral neuropathy, cauda equina syndrome, peroneal nerve paralysis, trochlear nerve disorder, abducens nerve disorder

Genetics & variants

GWAS landscape

8 GWAS associations across 18 studies. Top hits map to 1 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
chr16:53799847	1e-12		G	0.04
chr20:9707172	1e-08		C	2.31
chrX:145130985	3e-08		C	0.87
chr5:113049307	3e-08		G	0.08
chr2:69456325	4e-08		C	0.08
rs376385716	5e-08	ATP6V1G1P7 - RPL7P45	?
chr6:32180254	5e-08		G	0.1
rs148883532	6e-07	HCCS-DT	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90475842	Verma A	2024	79,540	333,394	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90477586	Verma A	2024	22,404	87,924	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90481058	Verma A	2024	22,404	87,924	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90435945	Zhou W	2018	12,592	394,067	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.
GCST90477584	Verma A	2024	10,091	44,659	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90473341	UK Biobank Whole-Genome Sequencing Consortium	2025	8,922	449,518	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90667856	UK Biobank Whole-Genome Sequencing Consortium	2025	8,922	449,518	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90473349	UK Biobank Whole-Genome Sequencing Consortium	2025	7,370	451,070	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90652167	Liu TY	2025	3,183	222,707	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.
GCST90651691	Liu TY	2025	2,417	222,707	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	1
Tier 4: intronic/intergenic	7

MAF distribution

Bucket	Variants
common (>=0.05)	1
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	7

Functional consequences

Consequence	Count
unknown	6
regulatory_region_variant	1
intron_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
chr16:53799847				0.424			1e-12	Tier 4: intronic/intergenic
chr20:9707172							1e-08	Tier 4: intronic/intergenic
chrX:145130985							3e-08	Tier 4: intronic/intergenic
chr5:113049307							3e-08	Tier 4: intronic/intergenic
chr2:69456325							4e-08	Tier 4: intronic/intergenic
rs376385716	13	104015642	T>C		regulatory_region_variant	ATP6V1G1P7 - RPL7P45	5e-08	Tier 3: regulatory
chr6:32180254							5e-08	Tier 4: intronic/intergenic
rs148883532	X	10957657	G>A,C		intron_variant	HCCS-DT	6e-07	Tier 4: intronic/intergenic

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

1 uncertain significance, 1 conflicting classifications of pathogenicity; other; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
9	NM_000410.4(HFE):c.845G>A (p.Cys282Tyr)	HFE	Conflicting classifications of pathogenicity; other; risk factor	criteria provided, conflicting classifications
870558	GRCh37/hg19 16q22.1(chr16:70185757-70416579)x3	DDX19B	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HFE	Orphanet:443057	Sporadic porphyria cutanea tarda
HFE	Orphanet:443062	Familial porphyria cutanea tarda
HFE	Orphanet:465508	Symptomatic form of HFE-related hemochromatosis
HFE	Orphanet:586	Cystic fibrosis
HFE	Orphanet:648581	Digenic hemochromatosis

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DDX19B	HGNC:2742	ENSG00000157349	Q9UMR2	ATP-dependent RNA helicase DDX19B	clinvar
HFE	HGNC:4886	ENSG00000010704	Q30201	Hereditary hemochromatosis protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DDX19B	ATP-dependent RNA helicase DDX19B	ATP-dependent RNA helicase involved in mRNA export from the nucleus.
HFE	Hereditary hemochromatosis protein	Binds to transferrin receptor (TFR) and reduces its affinity for iron-loaded transferrin.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	14.6×	0.135
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DDX19B	Enzyme (other)	yes	3.6.4.13	Helicase_C-like, DEAD/DEAH_box_helicase_dom, Helicase_ATP-bd
HFE	Antibody/Immunoglobulin	yes		MHC_I_a_a1/a2, Ig/MHC_CS, Ig_C1-set

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
left testis	1
right testis	1
olfactory bulb	1
stromal cell of endometrium	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DDX19B	185	ubiquitous	marker	left testis, right testis, calcaneal tendon
HFE	238	ubiquitous	marker	type B pancreatic cell, olfactory bulb, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HFE	1,569
DDX19B	1,567

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DDX19B	Q9UMR2	9
HFE	Q30201	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Transferrin endocytosis and recycling	1	368.4×	0.003	HFE

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of antigen processing and presentation of endogenous peptide antigen via MHC class I	1	8426.0×	0.003	HFE
regulation of iron ion transport	1	4213.0×	0.003	HFE
response to iron ion starvation	1	2808.7×	0.003	HFE
negative regulation of CD8-positive, alpha-beta T cell activation	1	2106.5×	0.003	HFE
negative regulation of T cell cytokine production	1	1203.7×	0.003	HFE
cellular response to iron ion	1	1203.7×	0.003	HFE
regulation of protein localization to cell surface	1	842.6×	0.003	HFE
transferrin transport	1	766.0×	0.003	HFE
urate metabolic process	1	766.0×	0.003	HFE
positive regulation of peptide hormone secretion	1	766.0×	0.003	HFE
hormone biosynthetic process	1	702.2×	0.003	HFE
response to iron ion	1	468.1×	0.005	HFE
negative regulation of ubiquitin-dependent protein catabolic process	1	421.3×	0.005	HFE
positive regulation of receptor-mediated endocytosis	1	401.2×	0.005	HFE
poly(A)+ mRNA export from nucleus	1	337.0×	0.005	DDX19B
multicellular organismal-level iron ion homeostasis	1	290.6×	0.006	HFE
negative regulation of proteasomal ubiquitin-dependent protein catabolic process	1	200.6×	0.008	HFE
positive regulation of SMAD protein signal transduction	1	191.5×	0.008	HFE
mRNA export from nucleus	1	147.8×	0.009	DDX19B
intracellular iron ion homeostasis	1	122.1×	0.011	HFE
receptor-mediated endocytosis	1	110.9×	0.011	HFE
BMP signaling pathway	1	100.3×	0.012	HFE
protein-containing complex assembly	1	56.9×	0.020	HFE
gene expression	1	39.9×	0.027	HFE
cell surface receptor signaling pathway	1	32.0×	0.032	HFE
positive regulation of gene expression	1	19.4×	0.051	HFE

Therapeutics

Drugs indicated or in trials for this disease

No drug has an approved disease-direct ChEMBL indication for this disease.

11 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Capsaicin	Phase 3
Carboplatin	Phase 3
Glutathione	Phase 3
Human Immunoglobulin G	Phase 3
Ketotifen	Phase 3
Paclitaxel	Phase 3
Pregabalin	Phase 3
Acetylcarnitine	Phase 2
Amitriptyline	Phase 2
Erenumab	Phase 2
Sulfasalazine	Phase 2

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DDX19B	0	0
HFE	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DDX19B	3.6.4.13	RNA helicase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	DDX19B, HFE
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
DDX19B	0	—
HFE	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 295.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	195
PHASE2	39
PHASE3	28
PHASE4	9
PHASE2/PHASE3	8
PHASE1/PHASE2	8
PHASE1	8

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07025005	PHASE4	RECRUITING	Fenofibrate Role in the Prophylaxis From Peripheral Neuropathy Induced by Bortezomib, Lenalidomide and Dexamethasone (VRd) Protocol in the Treatment of Patients With Multiple Myeloma (MM)
NCT00380965	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Chemotherapy-Induced Neuropathy
NCT00487981	PHASE4	TERMINATED	Spinal Cord Stimulation for Painful Diabetic Neuropathy
NCT00832572	PHASE4	TERMINATED	Study of Ranexa in Patients With Coronary Artery Disease and Painful Polyneuropathy
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT01192113	PHASE4	COMPLETED	Safety and Efficacy of Mecobalamin Injection in Peripheral Neuropathies Patients (Study JGAZSY091109)
NCT01373983	PHASE4	COMPLETED	Intrathecal Bolus Doses of Ziconotide
NCT01458015	PHASE4	TERMINATED	Tapentadol Versus Oxycodone - a Mechanism-based Treatment Approach in Neuropathic Pain
NCT02372149	PHASE4	UNKNOWN	IVIg for Demyelination in Diabetes Mellitus
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT07475065	PHASE2/PHASE3	NOT_YET_RECRUITING	The Effect of Oral DLBS1033 in Patients With Diabetic Polyneuropathy
NCT07504198	PHASE2/PHASE3	NOT_YET_RECRUITING	Neuroprotection of Memantine and Rosuvastatin
NCT00058071	PHASE3	COMPLETED	Amifostine in Treating Peripheral Neuropathy in Patients Who Have Received Chemotherapy for Cancer
NCT00061776	PHASE2/PHASE3	COMPLETED	NGX-4010 for the Treatment of Postherpetic Neuralgia
NCT00064623	PHASE3	COMPLETED	Study of NGX-4010 for the Treatment of Painful HIV-Associated Neuropathy
NCT00068081	PHASE3	COMPLETED	Controlled Study of NGX-4010 for the Treatment of Postherpetic Neuralgia
NCT00085761	PHASE3	TERMINATED	Study of NGX-4010 for Treatment of Painful HIV-Associated Neuropathy
NCT00115310	PHASE3	COMPLETED	Study of NGX-4010 for the Treatment of Postherpetic Neuralgia
NCT00125268	PHASE3	TERMINATED	Near Infrared Light for the Treatment of Painful Peripheral Neuropathy
NCT00195013	PHASE3	COMPLETED	Randomized Placebo-Controlled Trial of Glutamine for Breast Cancer Patients With Peripheral Neuropathy
NCT00232141	PHASE3	COMPLETED	Study of Pregabalin Versus Placebo in the Treatment of Nerve Pain Associated With HIV Neuropathy
NCT00264875	PHASE3	COMPLETED	Open Label Safety And Efficacy Study Of Pregabalin In Subjects With Nerve Pain Asociated With Human Immunodeficiency Virus (HIV) Neuropathy
NCT00300222	PHASE3	COMPLETED	Study of NGX-4010 for the Treatment of Postherpetic Neuralgia
NCT00321672	PHASE3	COMPLETED	Study of NGX-4010 for the Treatment of Painful HIV-Associated Neuropathy
NCT00369564	PHASE3	COMPLETED	Glutamic Acid in Reducing Nerve Damage Caused by Vincristine in Young Patients With Cancer
NCT00370656	PHASE2/PHASE3	COMPLETED	Effects of Pregabalin, Duloxetine & Amitriptyline on Pain & Sleep
NCT00471445	PHASE3	COMPLETED	Topical Amitriptyline and Ketamine Cream in Treating Peripheral Neuropathy Caused by Chemotherapy in Cancer Patients
NCT00489411	PHASE3	COMPLETED	Duloxetine in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer
NCT00710554	PHASE3	COMPLETED	A Study of Sativex® for Pain Relief of Peripheral Neuropathic Pain, Associated With Allodynia
NCT00711880	PHASE3	COMPLETED	A Study of Sativex® for Relief of Peripheral Neuropathic Pain Associated With Allodynia.
NCT00713323	PHASE3	COMPLETED	A Study to Compare the Safety and Tolerability of Sativex® in Patients With Neuropathic Pain.
NCT00713817	PHASE3	COMPLETED	A Study to Determine the Maintenance of Effect After Long-term Treatment of Sativex® in Subjects With Neuropathic Pain
NCT00872352	PHASE3	UNKNOWN	Evaluation of Bortezomib Induced Peripheral Neuropathy of Multiple Myeloma (MM) Patients
NCT01288937	PHASE3	TERMINATED	A Placebo Controlled, Randomized, Double Blind Trial of Milnacipran for the Treatment of Idiopathic Neuropathy Pain
NCT01465620	PHASE3	COMPLETED	Dietetic and Hygiene Measures in Metabolic Neuropathies: the Neurodiet Study
NCT02024191	PHASE3	UNKNOWN	The Role of Glutamine for Preventing Oxaliplatin-Induced Peripheral Neuropathy
NCT02217267	PHASE3	COMPLETED	Long Term Outcome After Serial Lidocaine Infusion in Peripheral Neuropathic Pain
NCT02590367	PHASE2/PHASE3	UNKNOWN	Estimate the Efficacy of HD6610 Granule for Oxaliplatin-induced Peripheral Neuropathy
NCT02936843	PHASE2/PHASE3	COMPLETED	Targeting Inflammation With Salsalate in Type 1 Diabetes Neuropathy
NCT05189535	PHASE2/PHASE3	COMPLETED	Prevention of Paclitaxel-Induced Peripheral Neuropathy in Breast Cancer Patients

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
AMITRIPTYLINE	4	7
CAPSAICIN	4	5
GLUTAMINE	4	5
BENZTROPINE	4	3
ACETYLCHOLINE	4	1
AMIFOSTINE	4	1
BORTEZOMIB	4	1
CILOSTAZOL	4	1
DULOXETINE HYDROCHLORIDE	4	1
ETHOSUXIMIDE	4	1
GABAPENTIN	4	1
HYALURONIDASE (HUMAN RECOMBINANT)	4	1
LENALIDOMIDE	4	1
LIDOCAINE HYDROCHLORIDE	4	1
MENTHOL	4	1
METHADONE	4	1
MEXILETINE HYDROCHLORIDE	4	1
MILNACIPRAN	4	1
MINOCYCLINE HYDROCHLORIDE	4	1
OXYCODONE	4	1
PENTOXIFYLLINE	4	1
PHENYTOIN	4	1
PHENYTOIN SODIUM	4	1
PIRENZEPINE	4	1
PYRILAMINE	4	1
RANOLAZINE	4	1
ROFLUMILAST	4	1
SELUMETINIB	4	1
TAPENTADOL	4	1
THIAMINE	4	1